Journal of Translational Medicine (Nov 2018)

Deficiency in interleukin-18 promotes differentiation of brown adipose tissue resulting in fat accumulation despite dyslipidemia

  • Kyosuke Yamanishi,
  • Seishi Maeda,
  • Sachi Kuwahara-Otani,
  • Takuya Hashimoto,
  • Kaoru Ikubo,
  • Keiichiro Mukai,
  • Keiji Nakasho,
  • Naomi Gamachi,
  • Yosif El-Darawish,
  • Wen Li,
  • Daisuke Okuzaki,
  • Yuko Watanabe,
  • Hiromichi Yamanishi,
  • Haruki Okamura,
  • Hisato Matsunaga

DOI
https://doi.org/10.1186/s12967-018-1684-3
Journal volume & issue
Vol. 16, no. 1
pp. 1 – 13

Abstract

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Abstract Background The cytokine, interleukin-18 (IL-18), was originally identified as an interferon-γ-inducing proinflammatory factor; however, there is increasing evidence suggesting that it has non-immunological effects on physiological functions. We have previously investigated the potential pathophysiological relationship between IL-18 and dyslipidemia, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, which were mediated by lipid energy imbalance. Therefore, herein we focused on brown adipocytes (BAs) and brown adipose tissue (BAT) related to energy consumption as non-shivering thermogenesis. Methods Il18 −/− male mice were generated on the C57Bl/6 background, and littermate C57Bl/6 Il18 +/+ male mice were used as controls. To reveal the direct effect of IL-18, primary cell cultures derived from both mice were established. Moreover, for molecular analysis, microarray, quantitative reverse transcription PCR and western blotting were performed using 6 and 12 weeks old mice. To evaluate the short- and long-term effects of IL-18 on BAT, recombinant IL-18 was administered for 2 and 12 weeks, respectively. Results Compared with Il18 +/+ mice, BAT of Il18 −/− mice showed earlier differentiation and lipid accumulation. To examine the direct effect of IL-18 on BAT, BA cell cultures were established. Myogenic factor 5-expressing adipose precursor cells were extracted from Il18 +/+ and Il18 −/− mice. PR domain containing 16 (PRDM16), a differentiation inducer, was strongly expressed in Il18 −/− BAs, and uncoupling protein 1, a thermogenic and differentiation marker, was upregulated, resulting in the promotion of BA differentiation. Moreover, PRDM16-dependent and independent molecules related to BAT function, such as fibroblast growth factor 21, were activated. These findings were confirmed by comparing Il18 +/+ and Il18 −/− mice at 6 and 12 weeks of age. Additional analyses of the molecular mechanisms influencing the ‘Quantity of adipocytes’ identified three associated genes, apolipoprotein C3 (Apoc3), insulin-induced gene 1 (Insig1) and vitamin D (1,25-dihydroxyvitamin D3) receptor (Vdr). Intravenous administration of IL-18 not only significantly improved the expression of some of these genes, but it also significantly decreased the adipocytes’ size. Conclusions This study demonstrated the critical function of IL-18 in differentiation and lipid metabolism in BAs. Furthermore, IL-18 may contribute to novel treatments by improving the energy imbalance.

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